Elsevier

Life Sciences

Volume 71, Issue 11, 2 August 2002, Pages 1227-1236
Life Sciences

Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats

https://doi.org/10.1016/S0024-3205(02)01848-9Get rights and content

Abstract

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.

Introduction

Recent studies have shown that duloxetine, a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, which does not possess anticholinergic or sympatholytic effects, produces significant increases in bladder capacity and external urethral sphincter EMG activity in a cat model of acetic acid-induced bladder irritation [1]. These effects were reversible with various serotonergic and adrenergic receptor antagonists, indicating the effects were mediated through inhibition of 5-HT and NE reuptake. Preliminary findings in placebo-controlled, double-blind trials have shown that duloxetine reduces the frequency of incontinent episodes and decreases the volume of leakage in women with stress urinary incontinence [2]. These findings indicate that inhibition of 5-HT and/or NE reuptake influence lower urinary tract function.

The aim of present study was to determine whether the inhibition of 5-HT reuptake or NE reuptake is the more important pharmacological property for the mediation of duloxetine's effects on the lower urinary tract. In previous studies of receptor antagonists, it appeared as if the 5-HT component was more important for the increase in bladder capacity, while both 5-HT and NE were important in mediating increases in sphincter EMG activity [1], [3], [4], [5], [6], [7], [8].

To achieve the above aim, s-norfluoxetine [9], [10] and thionisoxetine [11] were used for selective inhibition of 5-HT reuptake and NE reuptake, respectively. In addition to showing high affinity and great selectivity for their respective monoamine reuptake sites, both demonstrate low affinity for other neurotransmitter binding sites. For comparison to the selective reuptake inhibitors, the present study also examined the dual 5-HT and NE reuptake inhibitors venlafaxine [12], [13], [14] and duloxetine [1], [15].

Section snippets

Methods

Transvesical cystometrograms (CMGs) were performed first under conditions of saline infusion, then under conditions of acetic acid (0.5%) infusion, as previously described in detail [1]. Briefly, 26 adult female cats were anesthetized with alpha chloralose (50–75 mg/kg i.v., Sigma, St. Louis, MO). Following a midline laparotomy, the bladder was cannulated through the dome to allow infusion of fluids and recording of intravesical pressure. The urethra remained open to allow expulsion of fluids

Results

Under control conditions (Fig. 1A), large, rapid increases in intravesical pressure (30–50 cm H2O, i.e. micturition contractions) were recorded after infusion of saline (3–5 ml) into an initially empty bladder. Upon switching to infusion of acetic acid; bladder capacity, contraction amplitude, and contraction duration were reduced, while the contraction frequency was increased (Fig. 1B). Low levels of peri-urethral EMG activity were recorded during infusion of saline (<1–20 spikes per sec) as

Discussion

The present studies have shown that venlafaxine, a dual 5-HT and NE reuptake inhibitor [12], [13], [14], produces effects on bladder and sphincter function that are qualitatively quite similar to duloxetine [1], [15], a structurally-unrelated dual 5-HT and NE reuptake inhibitor. Although the effects of duloxetine and venlafaxine were qualitatively similar, duloxetine was about an order of magnitude more potent than venlafaxine. Both drugs exhibited similar efficacy in that bladder capacity and

Conclusions

Individual drugs with the combined properties of inhibiting serotonin and norepinephrine reuptake (i.e. duloxetine and venlafaxine) produce consistent inhibitory effects on bladder activity and facilitatory effects on external urethral sphincter activity. Surprisingly, combining selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors (e.g. s-norfluoxetine and nisoxetine) is ineffective or substantially less effective.

Acknowledgements

Eli Lilly and Co funded this work.

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